Abstract 913: Early detection of metastatic relapse and monitoring of therapeutic efficacy by ultra-deep sequencing of plasma cell-free DNA in patients with urothelial bladder carcinoma

Overtreatment with cisplatin-based chemotherapy is a major issue in the management of muscle-invasive bladder cancer (MIBC), and currently none of the reported biomarkers for predicting response have been implemented in the clinic. Here we perform a comprehensive multi-omics analysis (genomics, transcriptomics, epigenomics and proteomics) of 300 MIBC patients treated with chemotherapy (neoadjuvant or first-line) to identify molecular changes associated with treatment response. DNA-based associations with response converge on genomic instability driven by a high number of chromosomal alterations, indels, signature 5 mutations and/or BRCA2 mutations. Expression data identifies the basal/squamous gene expression subtype to be associated with poor response. Immune cell infiltration and high PD-1 protein expression are associated with treatment response. Through integration of genomic and transcriptomic data, we demonstrate patient stratification to groups of low and high likelihood of cisplatin-based response. This could pave the way for future patient selection following validation in prospective clinical trials.

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Molecular correlates of cisplatin-based chemotherapy response in muscle invasive bladder cancer by integrated multi-omics analysis

Taber

et al. 2020

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Circulating tumor DNA in neoadjuvant treated breast cancer reflects response and survival

Magbanua

Brown-Swigart

et al. 2020

Preprint

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Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for predicting pCR and risk of metastatic recurrence in 84 high-risk early breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL. Cell-free DNA (cfDNA) was isolated from 291 plasma samples collected at pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), or prior to surgery (T3). A personalized ctDNA test was designed to detect 16 patient-specific mutations (from whole exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. At T0, 61 of 84 (73%) patients were ctDNA-positive, which decreased over time (T1-35%; T2-14%; T3-9%). Patients who remained ctDNA-positive at T1 were significantly more likely to have residual disease after NAC (83% non-pCR) compared to those who cleared ctDNA (52% non-pCR; OR 4.33, P=0.012). After NAC, all patients who achieved pCR were ctDNA-negative (n=17, 100%). For those who did not achieve pCR (n=43), ctDNA-positive patients (14%) had significantly increased risk of metastatic recurrence (HR 10.4; 95% CI, 2.3–46.6); interestingly, patients who did not achieve pCR but were ctDNA-negative (86%) had excellent outcome, similar to those who achieved pCR (HR 1.4; 95% CI, 0.15–13.5). Lack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival regardless of pCR status. Personalized monitoring of ctDNA during NAC may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival.

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Cell-Free DNA: Hope and Potential Application in Cancer

Yan

Guo

Wang

et al. 2021

Front. Cell Dev. Biol.

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Cell-free DNA (cfDNA) is easily accessible in peripheral blood and can be used as biomarkers for cancer diagnostics, prognostics, and therapeutics. The applications of cfDNA in various areas of cancer management are attracting attention. In this review article, we discuss the potential relevance of using cfDNA analysis in clinical oncology, particularly in cancer screening, early diagnosis, therapeutic evaluation, monitoring disease progression; and determining disease prognosis.

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Abstract 913: Early detection of metastatic relapse and monitoring of therapeutic efficacy by ultra-deep sequencing of plasma cell-free DNA in patients with urothelial bladder carcinoma

Cited by 3 publications

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Molecular correlates of cisplatin-based chemotherapy response in muscle invasive bladder cancer by integrated multi-omics analysis

Molecular correlates of cisplatin-based chemotherapy response in muscle invasive bladder cancer by integrated multi-omics analysis

Circulating tumor DNA in neoadjuvant treated breast cancer reflects response and survival

Cell-Free DNA: Hope and Potential Application in Cancer

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